Despite availability of multiple antihypertensive drugs, which act on a variety of blood pressure-regulating systems, less than 40 percent of treated hypertensive patients have their blood pressures controlled. The overall objective of this research program is to elucidate the genetic basis of interindividual variation in responses to antihypertensive drug therapies. Such knowledge may reveal molecular mechanisms contributing to hypertension and aid in the tailoring of more effective antihypertensive drug therapy in individual patients. Blood pressure response to a thiazide diuretic depends on initial reduction of intravascular fluid volume due to inhibition of renal sodium reabsorption, and is subsequently opposed by counterregulatory activities of the renin-angiotensin-aldosterone system. Conversely, blood pressure response to an angiotensin H receptor blocker depends on inhibition of the renin-angiotensin-aldosterone system and is opposed by counterregulatory retention of sodium and fluid volume. In the first cycle of this project, we found that variants of the genes encoding angiotensin-converting enzyme and the G-proteins Beta3-subunit predicted blood pressure response to a thiazide diuretic in hypertensive African-Americans (n = 300) and non-Hispanic whites (n = 300). Aim 1 of this proposed renewal application will use the already-collected samples to determine whether variation in additional genes encoding the renin-angiotensin-aldosterone system, renal sodium transport systems, or related modulators of vasoconstriction and volume predict interindividual variation in blood pressure response to a thiazide diuretic. Aim 2 will determine whether variation in these same genes predicts interindividual variation in blood pressure response to an angiotensin II receptor blocker in newly recruited hypertensive African-Americans (n = 300) and non-Hispanic whites (n = 300). Aim 3 will use the combined samples from aims 1 and 2 (n=600 in each racial group) to contrast the identified predictors of response between these two antihypertensive drugs that differentially target the balance of vasoconstriction and volume maintaining blood pressure.